Daptomycin is a cyclic lipopeptide antibiotic indicated for the treatment of complicated skin and skin structure infections and bacteremia, including bacteremia with suspected or proven infective endocarditis. Daptomycin for injection can be administered intravenously to treat indicated infections caused by susceptible strains of multiple Gram-positive microorganisms including methicillin-resistant Staphylococcus aureus (MRSA). Daptomycin for injection (CUBICIN® by Cubist Pharmaceuticals, Inc., Lexington, MA) is supplied as a lyophilized powder that is reconstituted and compounded as a pharmaceutical composition for parenteral administration. The reconstituted daptomycin composition can be compounded as a pharmaceutical composition for parenteral administration, for example by combination with a medically appropriate amount of pharmaceutical diluent (e.g., 0.9% aqueous sodium chloride). The diluent can be the same or different. The parenteral pharmaceutical composition including daptomycin can be administered by intravenous infusion. The lyophilized powder containing daptomycin can take 15-45 minutes to reconstitute in a pharmaceutical diluent, depending on the reconstitution procedure.
Daptomycin (FIG. 1) can be derived from the fermentation product of the microorganism Streptomyces roseosporus with a feed of n-decanoic acid. Baltz in Biotechnology of Antibiotics. 2nd Ed., ed. W. R. Strohl (New York: Marcel Dekker, Inc.), 1997, pp. 415-435. Initial attempts to separate daptomycin from structurally similar components in the fermentation product lead to the identification of other structurally similar compounds including anhydro-daptomycin (FIG. 2), beta-isomer of daptomycin (FIG. 3) and a lactone hydrolysis product of daptomycin (FIG. 4). Anhydro-daptomycin (FIG. 2) can be formed while performing techniques to separate daptomycin from structurally similar components in the fermentation product. Rehydration of the anhydro-succinimido form produces a second degradation product that contains a β-aspartyl group and is designated the β-isomer form of daptomycin (FIG. 3). Kirsch et al. (Pharmaceutical Research, 6:387-393, 1989, “Kirsch”) disclose anhydro-daptomycin and the beta-isomer of daptomycin produced in the purification of daptomycin. Kirsch described methods to minimize the levels of anhydro-daptomycin and the β-isomer through manipulation of pH conditions and temperature conditions. However, Kirsch was unable to stabilize daptomycin and prevent the conversion of daptomycin to anhydro-daptomycin and its subsequent isomerization to β-isomer. Kirsch was also unable to prevent the degradation of daptomycin into other degradation products unrelated to anhydro-daptomycin and β-isomer.
U.S. Pat. No. 6,696,412 discloses several additional compounds present in the fermentation product from which daptomycin is derived, and provides methods for purifying daptomycin with increased purity. The additional compounds include the lactone hydrolysis product of daptomycin, having the chemical structure of FIG. 4. The daptomycin purification methods can include forming daptomycin micelles, removing low molecular weight contaminants by filtration, and then converting the daptomycin-containing micelle filtrate to a non-micelle state followed by anion exchange and reverse osmosis diafiltration to obtain the high-purity daptomycin that can then be lyophilized.
One measure of the chemical stability of daptomycin in the lyophilized daptomycin powder is the amount of daptomycin (FIG. 1) present in the reconstituted daptomycin composition relative to the amount of structurally similar compounds including anhydro-daptomycin (FIG. 2), beta-isomer of daptomycin (FIG. 3) and a lactone hydrolysis product of daptomycin (FIG. 4). The amount of daptomycin relative to the amount of these structurally similar compounds can be measured by high performance liquid chromatography (HPLC) after reconstitution in an aqueous diluent. The purity of daptomycin and amounts of structurally similar compounds (e.g., FIGS. 2-4) can be determined from peak areas obtained from HPLC (e.g., according to Example 4 herein) to provide a measure of daptomycin chemical stability in a solid form. The daptomycin purity and chemical stability can also be measured within the liquid reconstituted daptomycin composition over time as a measure of the reconstituted daptomycin chemical stability in a liquid form.
There is a need for solid lipopeptide compositions that rapidly reconstitute (e.g., in less than about 5 minutes) in a pharmaceutical diluent to form reconstituted lipopeptide compositions that can be compounded as pharmaceutical compositions. For example, to reconstitute a 500 mg vial of lyophilized daptomycin for injection (CUBICIN®), the lyophilized powder is combined with 10 mL of 0.9% aqueous sodium chloride, allowed to stand for 10 minutes (or more) and then gently rotated or swirled “a few minutes” to form the reconstituted daptomycin composition prior to formation to prepare a parenteral daptomycin pharmaceutical composition.
There is also a need for solid daptomycin compositions with improved chemical stability in the solid and/or reconstituted form (i.e., higher total percent daptomycin purity over time), providing advantages of longer shelf life, increased tolerance for more varied storage conditions (e.g., higher temperature or humidity) and increased chemical stability after reconstitution as a liquid formulation for parenteral administration.